PROJECT SUMMARY/ABSTRACT The social, economic and personal burden of Alzheimer's disease (AD) is rapidly climbing in the U.S. with diagnoses expected to more than double over the next three decades. At the same time, our understanding of the brain changes associated with AD is increasing exponentially, and promising interventions to slow or halt the progress of the disease are beginning to move from the laboratory into the clinic. In this context, the development of approaches to aid early detection of the transition from healthy aging to mild cognitive impairment (MCI) and AD is becoming critically important. The Alzheimer's Disease Neuroimaging Initiative (ADNI), funded by the National Institutes of Aging and Bioimaging and Bioengineering, was launched in 2005 to provide a large database data to develop diagnostic and prognostic biomarkers of AD. While the overarching goal of this longitudinal data collection initiative is to provide information and methods leading to effective treatment and prevention of AD, the significant promise of in vivo neuroimaging in this area has yet to be fully realized. However, we can now reliably detect AD in humans based on biological markers, sometimes decades before cognitive symptoms emerge based upon cerebrospinal fluid (CSF) concentrations of the amyloid beta peptide 1-42 (A?) The advent of the CSF A? biomarker opens a window for studying the pathological progression of AD at preclinical stages of disease in humans. We will capitalize on the rich array of multi-modal data available through the ADNI to integrate structural MRI and gene expression data, in combination with the CSF A? biomarker, to (i) identify cell-type specific degeneration of the cholinergic basal forebrain neurons across preclinical and mild cognitive impairment stages of AD, and (ii) map the subcortical-to-cortical spread of cholinergic degeneration by examining the covariance of structural degeneration between the basal forebrain and cortex.